Organ-Specific Regulation of Folic Acid Bioavailability by Bioactive Small Molecules from Whole Wheat Steamed Buns

Abstract The in vivo conversion of folic acid (FA) to its bioactive form is inefficient, and unmetabolized FA poses health concerns. This study investigates the regulatory mechanisms of active small molecules derived from whole wheat on FA intestinal absorption, liver metabolism, and brain accumulation. UPLC-Q-TOF-MS/MS was used to identify active constituents, combined with network pharmacology and molecular docking for target prediction, and a 48 day mouse study with multitissue quantification of FA and 5-methyltetrahydrofolate (5-MTHF). Network pharmacology revealed enrichment in endocytosis, organic acid transport, and blood–brain barrier pathways; molecular docking showed differential affinities for proton-coupled folic acid transporter, reduced folic acid carrier, folic acid receptor alpha, DHFR, and MTHFR. Animal studies confirmed that quercetin promoted intestinal absorption; D-calcium pantothenate enhanced liver 5-MTHF conversion; ferulic acid elevated circulating FA; and δ-tocopherol mediated brain-targeted accumulation of total folate (predominantly FA). These findings demonstrate that whole wheat-derived small molecules exert node-specific regulatory effects on folate metabolism, offering insights for developing FA-fortified foods.